Résumé
Tumor immunosubversion occurs through various mechanisms including the selective recruitment of CD4+ regulatory T cell (Treg) and the alteration of dendritic cell (DC) physiology. We reported that the presence of high number of both Treg and/or plasmacytoid DC (pDC) correlates with poor prognosis in breast (1-2) and ovarian carcinoma (3). We previously demonstrated that CCR4+ Treg are recruited from the periphery to the breast tumor through CCL22 production by breast tumor cells under exposure to IFNg, IL-1b and TNFa, consecutively to Macrophages and Natural killer cell detection of transformed cells (4). We report here that Tumor-associated Treg (Ta-Treg) are highly activated (GITRhighHLA-DRhighCD39high) and show a selective expression of high levels of ICOS, proliferate in situ (Ki-67+) but unlike blood Treg, did not proliferate ex vivo under CD3/CD28 co-stimulation in presence of IL-2. On the other hand, Ta-pDC expressed a partially activated phenotype but lacked their principal function, i.e., their type-I interferon production (key mediator of antiviral and tumoral immune responses), is strongly impaired. We show that Ta-Treg and Ta-pDC colocalize within lymphoid structures in vivo and demonstrate the unique capacity of Ta-pDC to favour proliferation of Ta-Treg and CD4+ T cells secreting IL-10. Of importance, this Treg amplification is strongly reduced by addition of exogenous IFNa. Furthermore, targeting ICOS with a neutralizing antibody suppresses Ta-Treg proliferation as well as IL-10 secretion in pDC/CD4+ T cell co-culture, demonstrating a role of ICOS-ICOS-L interaction in Ta-Treg proliferation mediated by Ta-pDC. In contrast, blocking ICOS does not impact T cell responses induced by mDC that, contrary to pDC, do not support Treg enrichment or high IL-10 secretion. Altogether these observations suggest that ICOS represents a therapeutic target in breast cancer that may allow to restore anti-tumor immunity. Grant supports: BCRF, Ligue nationale contre le cancer, ARC, Comité départementaux de la Ligue contre le cancer, INCa. 1. Treilleux I, Blay JY, Bendriss-Vermare N, et al. Dendritic cell infiltration and prognosis of early stage breast cancer. Clin Cancer Res. 2004; 10:7466-74. 2. Gobert M.., Caux C., Blay JY. and Ménétrier-Caux C. Treg recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Research 2009; 69:2000-9. 3. Labidi-Galy SI, Ray-Coquard I, Ménétrier-Caux C, Caux C, Blay JY and Bendriss-Vermare N. Systemic and local dysfunctions of pDC in ovarian carcinoma could contribute to immune tolerance. Cancer Res. 2011; 71:5423-34 4. Faget J., Blay J.Y., Caux C. and Ménétrier-Caux C. Early detection of tumor cells by innate immune cells leads to Treg recruitment through CCL22 production by tumor cells. Cancer Res. 2011; 71:6143-52 Citation Format: Authors. Abstract title [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5402. doi:1538-7445.AM2012-5402